Is BP Variability a Stronger Determinant of CV Outcomes Than Mean Pressure?

March 16, 2010

March 16, 2010 (Atlanta, Georgia) — New analyses from the ASCOT-BPLA trial show that variability in blood pressure is a much stronger determinant of both stroke and coronary disease outcome than average blood pressure throughout the trial. Senior author Dr Peter Sever (Imperial College, London, UK) reported the findings here at the American College of Cardiology 2010 Scientific Sessions, and they were part of a paper published online March 12, 2010 in Lancet Neurology [1] by Dr Peter M Rothwell (John Radcliffe Hospital, Oxford, UK) et al.

In a second paper, in the March 13, 2010 issue of the Lancet [2], also by Rothwell et al, post hoc analyses of randomized trials of cardiovascular disease showed that visit-to-visit variability of systolic blood pressure was a strong predictor of stroke, independent of mean blood pressure.

The Lancet Neurology paper is the first large analysis to illustrate this, says Sever, who is also a coauthor on the second paper: "Our study is based on 1.1 million measurements of BP, so it's hugely powerful; this story has been around, but it has not been investigated in any large-scale studies.

"There is no effect of mean BP on coronary outcome and a very small effect of average BP on stroke. While within-visit BP variability and variability assessed by 24-hour ambulatory BP monitoring [ABPM] did predict cardiovascular outcomes, the variation in BP as measured between visits--known as visit-to-visit variability--over a period of five years was by far the strongest predictor of cardiovascular outcomes," he noted.

CCBs Have Strongest Effect in Reducing BP Variability

Sever and colleagues also found in the Lancet Neurology paper that calcium-channel blockers (CCBs) cause a reduction in this BP variability, whereas beta blockers actually increased BP variability, and "this differential effect of drugs on the variability is an entirely new observation," he told heartwire . Adjusting for BP variability completely explained the differences in stroke and CHD outcomes between amlodipine-based and atenolol-based treatment in ASCOT, he noted.

Visit-to-visit variability over a period of five years was by far the strongest predictor of cardiovascular outcomes.

Meanwhile, a separate systematic review and meta-analysis, again published in the Lancet [3], by Dr Alastair JS Webb (John Radcliffe Hospital) et al, found that calcium antagonists and diuretics brought about the greatest reduction in visit-to-visit BP variability and were associated with the best stroke prevention, independently of mean systolic blood pressure. Beta blockers, which dose-dependently increased the variability of blood pressure, were the least effective in stroke prevention. Interindividual variation in systolic BP was also increased by ACE inhibitors and angiotensin-receptor blockers (ARBs) in this review, said Sever. The strongest effect was seen with CCBs; this "seems to be almost a unique property" of this drug class, he commented to heartwire .

We think the variability is telling us about stiffness, and we know that large vessels, when they become stiff, are harbingers of future vascular disease.

And Sever said there were some other interesting findings in his analysis: "If we look within the trial population, older age, history of smoking, diabetes, and a prior history of vascular disease all seemed to be associated with higher BP variability, and all those things are indicators of stiff blood vessels. We think the variability is telling us about stiffness, and we know that large vessels, when they become stiff, are harbingers of future vascular disease." The relation between long-term visit-to-visit variability in blood pressure and arterial stiffness should be explored to investigate whether these two variables measure the same underlying vascular pathological changes, he added.

Should Recommendations Be Changed? Not Yet

In a review accompanying his papers in the Lancet [4], Rothwell observes: "A widespread belief exists that underlying usual blood pressure can alone account for all blood-pressure–related risk of vascular events and for the benefits of antihypertensive drugs, and this notion has come to underpin all major clinical guidelines on diagnosis and treatment of hypertension. Other potentially informative measures, such as variability in clinic blood pressure or maximum blood pressure reached, have been neglected, and effects of antihypertensive drugs on such measures are largely unknown."

Asked whether he would now change recommendations for the treatment of hypertension, Sever told heartwire : "This is the question that everybody is now asking. Everyone has always disregarded transient changes in blood pressure, those random variations; you try to find a reason not to treat them, which is probably wrong; these variations are likely very important, because they are telling us about risk."

The take-home message is that you cannot ignore random variations in BP; they are telling you something about the risk of the individual.

Interestingly, he said, in the ASCOT-BPLA analysis, "if you had a lower intrapressure and higher variability, you were worse off than if you had a higher pressure in the trial with low variability. Now that is something that has not been considered before, but we will need others to look at the data. The take-home message is that you cannot ignore random variations in BP; they are telling you something about the risk of the individual, and therefore if they are not on CCBs you should be thinking about switching them to CCBs."

This particularly applies to patients with hypertension who are aged over 55, who constitute around 80% of those with hypertension, he says. "In those patients, CCBs and diuretics are more effective, and they should be used, as we say in the British guidelines, first. What we are now saying is that the CCBs are better than the diuretics, probably."

"Compelling" Findings That Might Set the Stage for a Major Change

In a Reflection and Reaction article accompanying the Lancet Neurology paper [5], Dr Philip B Gorelick (University of Illinois College of Medicine, Chicago) says: "In this issue of the Lancet Neurology, Rothwell and colleagues provide a thoughtful and provocative perspective on possible opposite effects of beta blockers and calcium-channel blockers on variability in blood pressure, which might explain their different effects on risk of stroke."

The researchers "are to be congratulated for bringing forth compelling findings that eventually might set the foundation for a major change in our practice of blood-pressure treatment for the prevention of stroke or other cardiovascular diseases," Gorelick continues. "Therefore, clinicians should give careful consideration to use of drugs associated with low variability in blood pressure."

Moreover, "the findings . . . might prove particularly important if the theory of central aortic blood pressure does not pan out or if both can be applied in clinical practice in a complementary manner, especially if the types of BP-lowering drugs that lower central aortic pressure and blood-pressure variability are from the same class or classes," Gorelick concludes.

Plausible Explanations for Unanswered Questions, But More Data Needed

And in a comment in the Lancet [6], Drs Bo Carlberg and Lars Hjalmar Lindholm (Umea University Hospital, Sweden) state: "Many believe that clinic blood pressure accounts for most of the risk and for the benefits of antihypertensive drugs. In the Lancet today, Peter Rothwell and coworkers challenge this notion. Importantly, [they] do not question the importance of mean blood pressure; rather, they make a strong argument for also measuring blood-pressure variability, because it supplements blood pressure very well as a risk factor."

They go on to note that most previous data on this subject come from studies of short-term variability of blood pressure, using 24-hour ambulatory monitoring or home blood-pressure recording devices, whereas the Lancet papers focus on long-term visit-to-visit variability of blood pressure.

More studies need to be done to better characterize the effects of different classes of antihypertensive drugs on long-term blood-pressure variability.

"Today, most hypertension guidelines recommend avoiding use of beta blockers as first-line drugs if there is no other compelling indication," Carlberg and Lindholm conclude. "The new analyses strengthen this recommendation and might prompt reconsideration by those who keep beta blockers as first-line treatment. However, more studies need to be done to better characterize the effects of different classes of antihypertensive drugs on long-term blood-pressure variability."

Pfizer was the major funding source of the main ASCOT trial, with additional support provided by Servier. Sever has received payment from Pfizer for lectures, travel, and accommodation and research grants from Pfizer and Servier. Rothwell has no conflicts of interest. Disclosures for other trial authors are listed in the papers. Gorelick has consulted for Novartis, Daiichi Sankyo, Boehringer Ingelheim and Pfizer. Carlberg and Lindholm report no conflicts of interest.

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